Development of PPL-138, a Novel Mixed NOP/Mu Partial Agonist for Treatment of CocaineUse Disorder

开发 PPL-138，一种用于治疗可卡因使用障碍的新型混合 NOP/Mu 部分激动剂

• 批准号: 10616932
• 负责人: Frances Rudnick Levin
• 金额: $ 268.02万
• 依托单位: PHOENIX PHARMALABS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616932
• 关键词: ADME Study; Affinity; Agonist; Alcohols; Analgesics; Animals; Attenuated; Behavior; Biological; Biological Availability; Blood Pressure; Brain; Buprenorphine; Businesses; Cardiovascular Physiology; Chemicals; Chronic; Clinical; Cocaine; Cocaine use disorder; Code; Constipation; Cross-Over Studies; Data; Development; Disease; Dose; Drug Interactions; Drug Kinetics; Drug abuse; Drug usage; Effectiveness; Eye; Family; Female; Financial Support; Formulation; Freeze Drying; Funding; Future; Goals; Heart Rate; Human; Human Volunteers; Husband; In Vitro; Laboratories; Ligands; Macaca mulatta; Methamphetamine; Methamphetamine use disorder; Naltrexone; Names; National Institute of Drug Abuse; Nicotine; Opioid; Opioid Receptor; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase I Clinical Trials; Polymorph; Powder dose form; Process; Public Health; Rattus; Relapse; Research Priority; Respiration; Rewards; Rivers; Rodent; Running; Safety; Self Administration; Societies; Sodium Chloride; Specific qualifier value; System; Testing; Therapeutic; Time; Toxic effect; Toxicogenetics; Toxicology; Treatment Efficacy; Universities; Work; addiction; alcohol abuse therapy; antagonist; cocaine self-administration; cocaine use; craving; design; drug discovery; drug of abuse; drug reward; effective therapy; efficacy study; experience; experimental study; first-in-human; forest; in vivo; inhibitor; male; manufacturing process development; meetings; methamphetamine abuse; mu receptors; nonhuman primate; novel; opioid use; pre-clinical; preclinical development; preclinical study; prevent; process optimization; product development; programs; psychostimulant; public-private partnership; pulmonary function; receptor; safety study; screening; sex; side effect; stability testing; stimulant abuse; success; therapeutic development

Abstract Currently, clinically used drug abuse medications exist for treatment of addiction to opiates, alcohol, and nicotine, but not psychostimulants such as cocaine and methamphetamine (METH). PPL-138 is a non-selective opioid receptor ligand with partial agonist activity at NOP and mu receptors, and antagonist activity at kappa and delta. This compound, initially synthesized by Drs. Lawrence Toll and Stephen Husbands in a NIDA funded effort, has now been licensed by Phoenix PharmaLabs (PPL), where Dr. Toll is a founder. This compound has been demonstrated to be a potent inhibitor of both cocaine and METH self-administration and reinstatement in rats, and to be not self-administered in rats or NHPs. Additional pharmacokinetic and safety studies in rodents and NHPs have demonstrated little to no effect on respiration, constipation, heart rate or blood pressure, up to high doses, thereby demonstrating a large apparent therapeutic window. It is our hypothesis that the increase in NOP receptor affinity and activity, compared to buprenorphine, renders PPL-138 less rewarding and better at blocking drug reward than buprenorphine, a compound demonstrated to reduce craving for psychostimulants. In this proposed project, PPL will focus on cocaine use disorder (CUD) with an eye on continuing to METH use disorder (MUD), in the future. To develop PPL-138, PPL has put together an experienced team with expertise in pharmacology, chemical manufacturing, IND-enabling preclinical studies, regulatory, and first in human studies and plan to take PPL-138 through each step, culminating in Phase I clinical trials. To accomplish these goals, experiments have been designed to encompass the following 5 aims. Specific Aim 1 studies performed at Wake Forest University will conduct final efficacy studies to determine whether PPL-138 is as effective in reducing cocaine self-administration and relapse in NHPs as it is in rats. Specific Aim 2, will be continue chemical manufacturing and encompass manufacturing process development and optimization, formulation, and GMP drug product development and manufacturing. Specific Aim 3 directed by drug discovery and toxicology consultants and performed primarily at Charles River Laboratories, will include a complete program of IND- enabling in vitro and in vivo GLP toxicology studies, as well as supporting ADME studies. These will build upon studies already completed by the previous licensee of this compound and current studies funded by PPL. Specific Aim 4 will be directed by ICON and devoted to development of regulatory processes and filing an IND. Finally, Specific Aim 5 will encompass first in human studies, directed by Dr. Frances Levin and run by ICON, with Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) studies followed by a Single Dose Crossover study in human volunteers. With the team of experts developing a very safe compound with a novel mechanism of action, we expect to determine in humans whether a NOP/mu partial agonist can safely and effectively reduce psychostimulant abuse. Importantly, PPL is committed to providing considerable financial support for this project to make this in the spirit of a Public/Private Partnership, as specified in the proposal.

抽象的 目前，存在临床使用的药物滥用药物以治疗对阿片类药物，酒精和尼古丁的成瘾治疗， 但没有可卡因和甲基苯丙胺等精神刺激剂（甲基苯丙胺）。 PPL-138是一种非选择性阿片类药物 具有部分激动剂活性在NOP和MU受体的受体配体，以及Kappa和Delta的拮抗剂活性。 该化合物，最初由DRS合成。劳伦斯·托尔（Lawrence Toll）和斯蒂芬（Stephen）的丈夫在NIDA资助的努力中已有 现在已获得Phoenix Pharmalabs（PPL）的许可，Toll博士是创始人。这个化合物已经 被证明是可卡因和甲基甲基自我处理和恢复的有效抑制剂， 并且不是在大鼠或NHP中自我管理。啮齿类动力学和安全研究 NHP对呼吸，便秘，心率或血压几乎没有影响，最高 剂量，从而证明了一个明显的明显治疗窗口。我们的假设是NOP的增加 与丁丙诺啡相比，受体亲和力和活性使PPL-138减少了奖励，更能阻止 与丁丙诺啡相比，药物奖励是一种降低对心理刺激剂的渴望的化合物。在这个 拟议的项目，PPL将重点关注可卡因使用障碍（CUD），并关注继续使用甲基甲基甲基苯丙胺障碍障碍 （泥）将来。为了开发PPL-138，PPL组成了一支具有专业知识的经验丰富的团队 药理学，化学制造，辅助临床前研究，调节性，首先是人类研究 并计划通过每个步骤进行PPL-138，最终在I期临床试验中达到最终形式。为了实现这些目标， 实验已设计为涵盖以下5个目标。特定的目标1研究 森林大学将进行最终效力研究，以确定PPL-138是否同样有效降低 可卡因自我给药和NHP中的复发，就像在大鼠中一样。特定的目标2将继续化学 制造和涵盖制造过程开发和优化，配方和GMP 药物开发和制造。特定目标3由药物发现和毒理学指导 顾问和主要在查尔斯河实验室进行的顾问，将包括一个完整的ind-Indophor计划 实现体外和体内GLP毒理学研究，并支持ADME研究。这些将基于 先前被许可人已经完成了该化合物和PPL资助的当前研究的研究。 特定目标4将由图标指导，并致力于开发监管过程并提交IND。 最后，特定的目标5将首先涵盖由弗朗西斯·莱文（Frances Levin）博士执导的人类研究，并由Icon运营， 单升剂量（SAD）和多个上升剂量（MAD）研究随后进行一次剂量 人类志愿者的跨界研究。专家团队开发了一个非常安全的化合物，并带有小说 作用机理，我们希望在人类中确定NOP/MU部分激动剂是否可以安全，并且 有效地减少精神刺激性虐待。重要的是，PPL致力于提供大量财务 支持该项目以公共/私人合作伙伴关系的精神来实现这一目标，如提案所指定的。